Macrophage­derived exosomes attenuate the susceptibility of oral squamous cell carcinoma cells to chemotherapeutic drugs through the AKT/GSK­3ß pathway.

Although chemotherapy is initially effective in debulking tumor mass in a number of different types of malignancy, tumor cells gradually acquire chemoresistance and frequently progress to advanced clinical stage. Accumulating evidence has indicated that the tumor sensitivity to several chemotherapeutic drugs is regulated by tumor stromal cells including macrophages. However, the role of macrophages in the efficacy of chemotherapeutics on oral squamous cell carcinoma (OSCC) cells is poorly understood. In the present study, the effects of macrophage­secreted exosomes on the sensitivity of OSCC cells towards chemotherapeutic agents were examined. Specifically, the effects of exosomes derived from THP­1 cells and primary human macrophages (PHM) were assessed on the chemosensitivity of OSC­4 cells treated with 5­fluorouracil (5­FU) and cis­diamminedichloroplatinum (CDDP). The THP­1­ and PHM­derived exosomes promoted dose­dependent proliferation, decreased the proliferative inhibitory effects of 5­FU and CDDP and decreased apoptosis in OSC­4 cells through activation of the AKT/glycogen synthase kinase­3ß signaling pathway. LY294002, a PI3K inhibitor, and MK­2206, an AKT inhibitor, were both able to suppress the observed decrease in sensitivity to chemotherapeutic agents induced by exosomes. Overall, the data from the present study suggested that the macrophage­derived exosomes may decrease the sensitivity to chemotherapeutic agents in OSCC cells. Thus, targeting the interaction between OSCC cells and macrophage­derived exosomes may be considered as a therapeutic approach to improve the chemosensitivity of the tumor microenvironment in oral cancer.

Ephrin-B2 reverse signaling regulates progression and lymph node metastasis of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck and frequently metastasizes to cervical lymph nodes. Aggressive local invasion and metastasis of OSCC are significant factors for poor prognosis. In this study, we investigated whether ephrin-B2 expressed in OSCC contributed to tumor progression and lymph node metastasis. Clinical specimens from patients with OSCC had robust ephrin-B2-positive tumor cells and ephrin-B2 protein level was associated with clinical stage, lymph node metastasis, and poor survival outcomes. We also determined that ephrin-B2 protein level was increased in OSCC cell lines compared to normal human oral keratinocytes and that its levels were associated with the migratory and invasive potential of OSCC cell lines. Transfection of an EFNB2-specific small interfering RNA (siRNA) into SAS-L1 cells significantly reduced proliferation, attachment, migration, and invasion through phosphorylation of the epidermal growth factor receptor, FAK, ERK1/2, p38, AKT, and JNK1/2 pathways. Furthermore, knockdown of EFNB2 significantly suppressed adhesion and transmigration of SAS-L1 cells toward human lymphatic endothelial cells. In addition, the growth rate of tumor xenografts and cervical lymph node metastases of OSCC were suppressed by local injection of EFNB2 siRNA. These results suggest that ephrin-B2 overexpression and activation of the ephrin-B2 reverse signaling pathway in tumor microenvironment in OSCC facilitates progression and lymph node metastasis via enhancement of malignant potential and interaction with surrounding cells.

Complete remission of Merkel cell carcinoma on the upper lip treated with radiation monotherapy and a literature review of Japanese cases.

Merkel cell carcinoma is a rare and aggressive neuroendocrine-derived skin cancer arising most commonly on the sun-exposed head and neck skin of elderly and immunocompromised patients. Although a combination of wide excision and adjuvant radiotherapy is the optimal therapeutic approach for Merkel cell carcinoma, radiation monotherapy has recently been recommended for unresectable tumors. We report here a case of Merkel cell carcinoma treated with radiation monotherapy and reviewed Merkel cell carcinoma cases treated with radiotherapy alone in Japan. A 75-year-old man was referred for treatment of a tumor on the upper lip with a swollen submental lymph node. The histopathological diagnosis from biopsied material was Merkel cell carcinoma (T3N1bM0, stage IIIB). The submental lymph node was extirpated and radiation monotherapy was applied according to the 2014 National Comprehensive Cancer Network Guidelines because the Eastern Cooperative Oncology Group Performance Status of the patient was grade 3 and the patient and his family did not desire surgery. The primary site and bilateral upper neck regions were irradiated with 45 Gy followed by 20 Gy irradiation for the primary site alone. Three months after radiotherapy, the tumor seemed to have completely remitted. Approximately 1 year after radiotherapy, no evidence of local recurrence or late metastasis has been noted. Radiation monotherapy should be considered as a curative treatment for Merkel cell carcinoma, particularly in situations where extensive surgery is not favored.